N-2-hydroxy-1-(p-sulfamylbenzoyl) ethylacylamides



Unite N-Z-HYDROXY-l-(p-SULFAMYLBENZOYL) ETHYLACYLAMDES States Patent Walter A. Gregory, Wilmington, DeL, assignor to E. I.

du Pont de Nemours and Company, Wilmington, DeL, av corporation of Delaware No Drawing. Application May 27, 1954, Serial No. 432,890

6 Claims. (Cl. 260-556) This invention relates to N-[Z-hydroxy-l-(p-sulfamylbenzoyDethyllacetamide and related compounds and to their preparation.

application is a continuation-impart of' my copend'ing application Serial No; 296,959, filed July 2,

1952, now Patent No. 2,680,135;

The compounds of the invention are represented by the formula bromoacetyl and the like,

The terms lower alkyl and lower alkoxy as used herein include all alkyl and alkoxy radicals containing not more than six carton atoms.

Illusrative of the compounds of the invention are:

-Alpha,alpha' dichloro N [2" hydroxy I (p methylsulfamylbenzoyl )ethyl] acetamide- Alpha ,alpha; dibromo N [2 h-yd'roxy 1' (p' dimethylsulfamylbenzoyl ethyl lacetamid'e Allphaalpha dichloro N [2 i hydroxy 1' (p ethylsulfamylbenzoyl) ethyl] acetamide Alpha,alpha dibromo N [2 hydroxy l (p propylsulfamylbenzoyl) ethyl]acetamide Adpha,alp'ha dibromo. N (2 hydroxy 1. (p [N 62 hydroxyethyl) sul-famyllahenzoyltlethyl) acetamide Alpha,alpha dichloro N (2 hydroxy 1 (p [N,N bis'tZ --hyd-roxyethyl)sulfamylTb'enzoyDethyl) acetamide Alpha,alpha dichloro N [2 hydroxy l (p sulfamyIbenzoylJethyl]acetamide "Alphaalpha dichloro N E2 hydroxy l (p diethylsulfamylbenzoyl)ethylTacetamide 'Alpha,alpha dichloro- N [2 hydroxy' 1 (3 chloro 4- -methylsulfamyl)ethylJacetamide' -Alplia,alpha d'ibromo N [2 hydroxy l (3 methyi 4- methylsulfamylbenzoylj ethyl] acetamide' Alphagalpha dichl'oro N [2 hydroxy l (3* ethoxy a ethylsulfarn-ylhenzoyl) ethyflacetarnide" mphagalpha dichloro N ['2' hydroxy 1 (\2-- Bromo- 4 dimethylsulfamylbenzoyl') ethyl] acetami'de Alpha,alpha dichloro N [2' hydroxy 11- (2- Alpli'aalpha diehloro N [2 hydroxy l ('2' methoxy 4 sulfamylbenzoyl)ethyllacetamide N [2 hydroxy 1 (p methylsulfamylhenzoyl)ethyl]- acetamide Alpha chloro N [2 hydroxy 1 i (p methyl sulfamyl benzoyl) ethyl] acetamide 2,726,265 '7 Patented Dec. 6, 1955 Alpha bromo N- [2 hydroxy 1 (p methyl sulfamylbenzoyl)ethyllacetamide N [2- hydroxy -1- tpmethylsulfamylbenzoylj'ethyl] propionamide Alpha,alpha ,alpha trifluoro N [2 hydroxy l (p methylsulfamylbenzoyl)ethyl] acetamide The compounds represented by Formula 1 may exist in optical isomeric form. In other words, the amides may exist as the (d) or (I) form or as a racemic mixture.

It will be understood that where no notation appears with a structural formula or with a chemical name the formula or name is to be interpreted in its generic sense; that is, as representing the (I) or (d) isomers in separated form as well as the (a'l) optical racemate. In other words, a formula or name represents not only the unresolved mixture of isomers but also the individual isomers and racemate.

The compounds of the invention can be prepared by reacting a nitro'gen containing compound of'the formula \NH R2 where R; and R2 have the samets'ignificance as in Formula 1 with a p (alpha acetamido beta hydroxy propionyl)benzenesulfonyl fluoride having the formula where R3 and acyl have the same significance as in Formula 1.

The substituted benzenesu'lfonyl fluorides used in the preparation of the compounds of the invention and represented by Formula 3 are fully described and claimed in my copending application Serial No. 296,960, filed July 2', 1952', new Patent No. 2,680,134; The preparationof the fl'u'orosultonylp'henylamidml ,3' propane'diols is also described and claimed in this same copending application Seria'laNo: 296,960, new PatentN'o. 2,68%134:

In brief, the fiuorosulfonylphenylamidopropanedinls are prepared from p-fiuorosulfonylacetophenone or related compounds of the formula 0 O F s l ca by a series of six steps which consist on halogenat-ion', addition of hexarnethylenetetramine, sulfurous acid treatment, acidification, aeylatio'n, and hydroxyrnethylation.

An alternative route cam he diagrammatically represented as follows:

where R1, R2, R3 and acyl have the same significance as in formula 1 and X represents a chloro, bromo or iodo radical.

Step 1 of this alternative process involves converting a compound of the formula to an acetophenone of the formula using potassium permanganate and magnesium nitrate hexahydrate. The resulting substituted acetophenone is halogenated in Step 2, preferably in glacial acetic acid, to yield a compound having the formula 4 for instance, anisole, with hexamethylenetetramine to yield a hexamethylenetetraminium halide of formula This product may be hydrolyzed directly to the aminoketone hydrochloride of Step 5, preferably in an aqueous alcoholic medium. It is also possible to proceed directly to the sulfite without isolation of the hexamethylenetetraminium halide using sulfur dioxide and water as shown on the diagram as Step 4. The substituted sulfamylacetophenone sulfite resulting from Step 4 can be readily converted into the substituted sulfamylacetophenone hydrochloride using hydrochloric acid (Step 5 Step 6 comprises N-acylating the amine hydrochloride compound of Step 5. This step is preferably carried out using dichloroacetyl chloride but similar acid halides or acetic anhydride in the presence of a weak base, for instance, sodium acetate, may be used.

The amide derivative produced in accordance with Step 6 of my process is then subjected to an aldol type of condensation to yield a compound having the formula This condensation is preferably carried out in an alcoholic medium, for example, ethanol or methanol, using sodium bicarbonate, or potassium carbonate, and an aqueous formaldehyde of 36-38% concentration.

The compounds of my invention are useful as chemical intermediates for antibacterial agents, such as l-(p-dimethylsulfamylphenyl) 2 (alpha,alpha-dichloroacetamido)-l,3-propanediol and related compounds of my parent application. They are also useful in their own right as chemotherapeutic agents. The compounds of the present invention have been found to have antifungal and antibacterial activity against such organisms as Candida albicans and Streptococcus agalactiae.

In order to more fully understand the invention, reference should be had to the following illustrative examples:

EXAMPLE 1 Preparation of alpha,alpha-dichl0ro-N-[Z-hydroxy-I-(pdimethylsulfamylbenzoyl)-ethyl]acetamide NHCOCHCI:

To a stirred solution of 640 g. of dimethylamine in 2 liters of water at 10 C. there is added 990 g. of p-ethyl' benzenesulfonyl chloride. The temperature of the reaction mixture is kept between 10-15 C. during the chloride addition. At the end of the addition the temperature of the mixture is raised to 40 C. .and maintained at 40 C. for a period of one-half hour. The resulting solution is cooled and then extracted with chloroform. The chloroform extract is distilled. The product, p-dimethylsulfamylethylbenzene, is collected at a temperature of from 178-180 C. at 10 mm. pressure. It is a white crystalline solid melting 49-51 C.

The yield of p-dimethylsulfamylethylbenzene is 864 g. IT'lie formula of p-dimethylsulfamylethylbenzene is shown e ow:

C a A solution of 800 g. of p-dimethylsulfamylethylbenzene in 9.5- liters of acetoneis' added to a. mixture: consisting of 570 g. of potassium permanganate and 1530 g. of magnesium: nitrate hexahydrate in 9.5litersof water warmed to a temperature of 50 6.. Thereaction mixture is stirred at a temperature (@150 C. for a period of two hours. Then an additional 220.3,. of: potassium permanganate is added. The reaction is allowed to continue for three hours.

The excess permanganate is'reduoed by adding sodium sulfite until the filtered solution is colorless. The manganese dioxide is removed by filtering the solution with the use of Celite Filter Aid. The filtrate, which is separated asa semi-crystalline mass,- amounts to 794 g. The product can be purifiedby successive. crystallizations from carbon tetrachloride or benzene, or it may be distilled under reduced pressure. A. substantial quantity of unoxidized starting material is recovered. The product, p-dimethylsulfamylacetophenone, is a white crystal-line solid melting 102-40 3" 0., and has the'followingstructural formula:

Analysis.--Calc for Ciel-113N038: C,, 52.84;, H, 5.76; N, 6.16.. Found; C,.52.79;.H,. 5.88;.N, 6.07.

A solution of 261 g. of-p-dimethylsulfamylacetophenone in 1.5 liters of glacial acetic acid is stirred at a temperature of 1720 C. as 183.8 g. of. bromine is added. An initial induction period is required for the bromination to start. This varies from minutes to several hours. After the solution decolorizes, the bromine is added dropwise over a. period of two hours- The: resulting: mixture is; then poured into 5 liters ofice andiwatem. The product separates as an oil, which soon crystallizes. amounts to 349 g. and has a melting range of 7580 C. After the crude product is recrystallized twice from benzene, 244 g.. of white crystalline material is obtained. M. P. 90-92 C. Additional product is: recoverable from the filtrate.

The. product, alpha-bromo p-(dimethylsulzfamyl) -acetophenone, has the followingstructural formula:

A nalysisa-Calcd. for .CroHreBtfNOhS: Br, 262.01. Found: Br, 25.9l...

A solution of 244 g. of alpha-bromo-p-(dimethylsulfamyl)acetophenone in 1 liter of anisole is stirred at normal room temperature as 112.2 g. of hexarnethylenetetramine is added. The temperature to the reaction mixture rises to 41 C. and the stirring is continued for a period of two hours. The anisole slurry is then poured into 3 liters of ice water to which 600 g. of sulfur dioxide has been added. After a period of 15 minutes, the slurry is filtered, and the solid is collected and washed with absolute ethanol and ether. A yield of 196 g. of a white powdery product is obtained. A further 135 g. of product separates from the filtrate on evaporation. The product, alpha-(hydroxymethylamino) p dimethylsulfamylacetophenone sulfite, has the following formula:

A suspension of 197 g. of alpha-(hydroxymethylamino)- p-(dimethylsulfamyl)acetophenone sulfite in a solution consisting of 197 cc. of concentrated hydrochloric acid and 394 cc. of absolute ethanol is stirred and refluxed for a period of 30 minutes. Sulfur dioxide is evolved and a substantial portion of the solid dissolves. The hot solution is filtered to remove any ammonium chloride present. On cooling the filtrate, crystals appear. They are col- "llheproduct '6 lected on a filter, washedwith-ether and dried. A furthe: quantity of product is. obtained .by concentrating the filtrate. A total yi'eld ofi 135g. of'light tan needles'is obtained. The product is alpha-amino-p-(dimethylsulfamyl) acetophenone hydrochloride and has the structure:

A suspension of 130 g-,. of alpha-amino-p-(dimethylsulfamyllaeetophenone hydrochloride in 360 cc. of freshly distilled dichloroacetyl chloride is stirred as the temperature of the suspension is raised to reflux. Hydrogen chloride is rapidly evolved and. the solid dissolves. After refluxing the solution for a-periodof 30 minutes, the solution is cooled. The product is filtered, collected and washed with benzene and" ether. The yield of productv is-14i8 g. andhasa melting point ofi192-195" C. After two recrystal lizations. of the crude product from acetonitrile, 127 g. of white crystalline material is obtained. M. P. 196-198" C; This material is alpha, alpha dichloro N' (p dimethylsulfamylphenacyl)- acetamide. Its formula is:

Analysis.-Caled-.. for Cr2Hr4ClzNaO4S: N', 719-3. Found-z; N, 7.79..

A suspension of 72.6 g. of alp-lrag. alpha-dichloro-N- (p-dimethylsulfamylphenacyl)acetamide in 320 cc. of ethanol containinglufl g'. of. potassium carbonate and 25.6 cc. of 36% aqueous formaldehyde is stirred at a temperature: of! 3-537-" C. for a period ofifour hours. The warm solution is filtered free of a trace of unreacted material, and the filtrate made: acid by adding dilute hydrochloric acid. The filtrate is diluted with 1 liter of benzene and concentrated under reduced pres sure- The: desire'd pro'du ct crystallizes and the crystals are collected and washed withbenzene. A yield of 34" g. of white crystalline product (ML P. 90"-100'' C.) is obtained; Al further'quantity of" 38 g. of crude material is obtained by diluting the filtrate with benzene and concentrating fort-hen The product? is a benzene solvate of alpha, alpha-dichloro-N-EZ-hydroxy P- (p -dimethyfsul famylbenzoyl)-ethyl]acetamide. The unsolvated compound may be obtained by heating the benzene solvate under reduced pressure.

EXAMPLE 2 Preparation of alpha, alpha-dichloro-N-[Z-hydroxy-I-(psulfamylbenzoybethyl] -acetamide Concentrated aqueous ammonia (50 cc.) is stirred with cooling to 10 C. as 5 g. of p-[alpha-(alpha,alphadichloroacetamido) beta hydroxypropionyl]benzenesulfonyl fluoride, prepared as described in my copending U. S. application, Serial No. 296,960, filed July 2, 1952,

7 EXAMPLE 3 Preparation of alpha,alpha-dichlor-N-[Z-hydroxy-I-(pmethylsulfamylbenzoyl)-ethyl]acetamide O NHCOCHC]:

Twenty-five cc. of 25% aqueous methyl amine is cooled to C. and 5 g. of p-[alpha-(alpha,a1pba-dichloroacetamido) beta hydroxypropionyl]benzenesulfonyl fluoride is added slowly with good stirring. After the addition is complete (about 45 minutes), the mixture is stirred for an additional hour. The methylamine is distilled off under reduced pressure and the residue stirred with water. The pH of the mixture is adjusted to 4.0. The desired product may be extracted with ethyl acetate.

EXAMPLE 4 Preparation of N [2 hydroxy 1 (p ethylsulfamylbenzoyl) ethyl] acetamide O NHCOCH;

Anhydrous ethyl amine (30 cc.) is stirred at 5 C. as 5 g. of p-(alpha-acetamido-beta-hydroxypropionyl)benzenesulfonyl fluoride is slowly added. The addition is made over a period of 30 minutes and stirring is continued for two hours. The ethyl amine is then distilled off under reduced pressure, and the residue taken up in water and the aqueous extract is brought to pH 4.0. The desired product crystallizes and may be purified by crystallization from ethanol.

I claim:

1. A compound of the formula 8 4. Alpha,alpha-dichloro-N-[Z-hydroxy-l-(p-methylsulfamylbenzoyl) ethyl] acetamide.

5. Alpha,alpha-dichloro-N-[Z-hydroxy-l-(p-ethylsulfamylbenzoyl) ethyl] acetamide.

6. A process which comprises the steps of mixing a compound of the formula where R1 and R2 are members of the class consisting of hydrogen, lower alkyl and hydroxyethyl radicals, R3 is a member of the class consisting of hydrogen, halogen, lower alkyl and lower alkoxyl radicals, and X is halogen, widi hexamethylenetetramine and hydrolyzing the salt thus formed with hydrochloric acid in an aqueous alcoholic mediiun to a compound of the formula R: R1\ 0 O N-S L-CHPNHPHCI P 0 mixing the latter compound with a carboxylic acid acylating agent, recovering a compound of the formula R; 0 0 H N-S iiCH,N-Ac l thus formed, reacting the latter product with formaldehyde in the presence of dilute alkali to obtain a compound of the formula where R1 and R2 have the same significance as above and acyl is a carboxylic acid acyl radical.

References Cited in the file of this patent UNITED STATES PATENTS Gregory June 1, 1954 Gregory June 1, 1954 

1. A COMPOUND OF THE FORMULA 